Apparatus for and Method of Terminating a High Frequency Arrhythmic Electric State of a Biological Tissue

ABSTRACT

For terminating a high frequency arrhythmic electric state of a biological tissue an electric signal representative of the present electric state of the biological tissue is obtained. From the electric signal a dominant frequency of the present electric state is determined, and from the dominant frequency it is determined whether the present electric state of the biological tissue is a high frequency arrhythmic electric state. Further, a dominance level indicative of how dominant the dominant frequency is in the high frequency arrhythmic electric state is determined from the electric signal. Depending on the at least one dominant frequency, at least one series of electric pulses at intervals is generated. The electric pulses are applied to the biological tissue starting at a point in time at which the dominance level exceeds a predefined threshold value for the biological tissue being in a determined high frequency arrhythmic electric state.

FIELD OF THE INVENTION

The present invention generally relates to an apparatus for and to amethod of terminating a high frequency arrhythmic electric state of abiological tissue. In general, the tissue may be any biological tissue.More particular, it is muscle or nerve tissue. Particularly, thebiological tissue is heart or brain tissue. Even more particularly, itis a heart or a brain of a living animal which may be a human.

BACKGROUND OF THE INVENTION

In a normal heart, regular waves of electric depolarization of thecellular membrane propagate to trigger the mechanical contractions.Life-threatening arrhythmias of the heart are typically associated withhigh-frequency rotating electric field waves or spirals. One standardmethod of terminating arrhythmias, often referred to as defibrillation,is applying a high intensity electric shock to the heart. The highvoltage of up to several thousand volt and the resulting currents ofsome amperes, however, may cause serious damages to the heart andneighboring tissue. Further, defibrillation is painful for the patientwhich limits the acceptance of implanted defibrillators. Nevertheless,up to now, implanting such defibrillators are the method of choice withpatients at risk for life-threatening arrhythmias.

Another established therapy of cardiac arrhythmias is anti-tachycardiapacing (ATP). In ATP the heart is paced faster than its intrinsic ratein the case of ventricular tachycardia. However, ATP fails to terminatehigh-frequency arrhythmias and fully developed ventricular fibrillation.

Patent application publication US 2006/0100670 A1 proposes cardiacstimulation methods and systems that provide for multiple pulsedefibrillation. These methods and systems involve sensing a fibrillationevent, determining a fibrillation cycle length associated with thefibrillation event, and delivering a plurality of defibrillation pulsesto treat the fibrillation event. The defibrillation pulses are deliveredusing a combination of subcutaneous and non-intrathoracic electrodes.Delivery of each defibrillation waveform subsequent to a firstdefibrillation waveform is separated in time by a delay associated withthe fibrillation cycle length. Particularly, delays betweendefibrillation waveform delivery are associated with a percentage of thefibrillation cycle length. The actual number of defibrillation pulsesdelivered in the embodiments of US 2006/0100670 A1 is 2 or 3,particularly 2. The actual delay between the individual pulses isbetween about 50% and about 125% of the average cycle length andtypically it is between about 75% and about 100% of the average cyclelength, where the cardiac response to multiple separated pulses issimilar to the cardiac response to a single pulse. This region, which isconsidered as similar to a region of constructive interference for thecardiac response to the separated response to the separated pulses, istold to provide opportunities for improved efficacy of defibrillationand/or decreased energy requirements for defibrillation systems.

A. Pumir et al.: “Wave Emission from Heterogeneities Opens a Way toControlling Chaos in the Heart” (PRL 99, 208101 (2007)) suggest to usewave emission from heterogeneities (WEH) induced by periodic pulses ofan electric field as a method of chaos control of waves in the heart.This method is said to be more effective than ATP and to require muchless energy than the defibrillating shock. Particularly, the singlepulses are of such a low electric field that they do not terminate arotating wave, but the train of pulses applied in WEH can.

There is still a need for an easily workable regime of terminating ahigh frequency arrhythmic electric state of a biological tissue with lowelectric field pulses causing as little tissue damage and pain aspossible.

SUMMARY OF THE INVENTION

The present invention relates to an apparatus for terminating a highfrequency arrhythmic electric state of a biological tissue, theapparatus comprising: at least one sensor for providing an electricsignal representative of the present electric state of the biologicaltissue; a determination unit which determines from the electric signalat least one dominant frequency of the present electric state of thebiological tissue, and which determines from the at least one dominantfrequency whether the present electric state of the biological tissue isa high frequency arrhythmic electric state; an electric pulse generatorfor generating at least one series of electric pulses at intervalsdepending on the at least one dominant frequency; and at least oneelectrode connected to the pulse generator for applying the electricpulses to the biological tissue. For terminating a determined highfrequency arrhythmic electric state of the biological tissue, thedetermination unit determines from the electric signal a dominance levelindicative of how dominant the at least one dominant frequency is in thehigh frequency arrhythmic electric state; and triggers the electricpulse generator to generate the at least one series of electric pulsesstarting at a point in time at which the dominance level determinedexceeds a predefined threshold value.

In another aspect, the present invention relates to a method ofterminating a high frequency arrhythmic electric state of a biologicaltissue, the method comprising: obtaining a electric signalrepresentative of the present electric state of the biological tissue;determining from the electric signal at least one dominant frequency ofthe present electric state of the biological tissue; determining fromthe at least one dominant frequency whether the present electric stateof the biological tissue is a high frequency arrhythmic electric state;determining from the electric signal a dominance level indicative of howdominant the at least one dominant frequency is in the high frequencyarrhythmic electric state; generating at least one series of electricpulses at intervals depending on the at least one dominant frequency;and applying the electric pulses to the biological tissue starting at apoint in time at which the dominance level exceeds a predefinedthreshold value for the biological tissue being in a determined highfrequency arrhythmic electric state.

In another aspect, the present invention relates to an apparatus forterminating an atrial fibrillation of an atrium of a heart, theapparatus comprising: at least one sensor configured to provide anelectric signal representative of the present electric state of theatrium; a determination unit configured to determine from the electricalsignal whether the present electric state of the biological tissue is anatrial fibrillation; an electric pulse generator for generating at leastone series of electric low energy anti-fibrillation pacing pulses atintervals depending on the electrical signal; at least one electrodeconnected to the pulse generator configured to apply the low energyanti-fibrillation pacing pulses to the atrium; at least one furthersensor configured to provide a further electric signal representative ofan ventricular action potential of a ventricle of the heart; a furtherelectric pulse generator configured to generate electric pacing pulses;at least one further electrode connected to the further pulse generatorand configured to apply the electric pacing pulses to the ventricle; anda synchronization unit configured to synchronize the at least one seriesof low energy anti-fibrillation pacing pulses with the electric pacingpulses such that no low energy anti-fibrillation pacing pulse of the atleast one series of low energy anti-fibrillation pacing pulses isapplied in a vulnerable window during which the ventricle is susceptibleto shock-induced ventricular fibrillation.

In yet another aspect, the present invention relates to a method ofterminating an atrial fibrillation of an atrium of a heart, the methodcomprising: obtaining a electric signal representative of the presentelectric state of the atrium; determining from the electric signalwhether the present electric state of the biological tissue is an atrialfibrillation; generating at least one series of electric low energyanti-fibrillation pacing pulses at intervals depending on the electricsignal; obtaining a further electric signal representative of anventricular action potential of a ventricle of the heart; generatingelectric pacing pulses; applying the electric pacing pulses to theventricle; generating at least one series of electric low energyanti-fibrillation pacing pulses at intervals depending on the electricsignal; applying the low energy anti-fibrillation pacing pulses to theatrium; and synchronizing the at least one series of low energyanti-fibrillation pacing pulses with the electric pacing pulses suchthat no low energy anti-fibrillation pacing pulse of the at least oneseries of low energy anti-fibrillation pacing pulses is applied in avulnerable window during which the ventricle is susceptible toshock-induced ventricular fibrillation.

Other features and advantages of the present invention will becomeapparent to one with skill in the art upon examination of the followingdrawings and the detailed description. It is intended that all suchadditional features and advantages be included herein within the scopeof the present invention, as defined by the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be better understood with reference to the followingdrawings. The components in the drawings are not necessarily to scale,emphasis instead being placed upon clearly illustrating the principlesof the present invention. In the drawings, like reference numeralsdesignate corresponding parts throughout the several views.

FIG. 1 illustrates a basic setup of an apparatus for terminating a highfrequency arrhythmic electric state of a biological tissue.

FIG. 2 is a block diagram of a method of terminating a high frequencyarrhythmic electric state of a biological tissue applying electricpulses to the biological tissue using the apparatus according to FIG. 1.

FIG. 3 illustrates a concept of determining an optimum starting pointfor applying the electric pulses to the biological tissue in the methodaccording to FIG. 2.

FIG. 4 illustrates a concept of determining a minimum suitable voltageof the electric pulses to be applied in the method according to FIG. 2.

FIG. 5 illustrates a concept of raster scanning the phase space of adominant frequency of the arrhythmic electrical state in the methodaccording to FIG. 2.

FIG. 6 illustrates another concept of raster scanning the phase space ofa dominant frequency of the arrhythmic electrical state in the methodaccording to FIG. 2.

FIG. 7 illustrates a concept of suppressing atrial fibrillation (AF)without shock-induction of ventricular fibrillation (VF); and

FIG. 8 illustrates a more detailed illustrates a concept of determiningan optimum starting point for applying the electric pulses to thebiological tissue in the method according to FIG. 2.

DETAILED DESCRIPTION

In order to determine a high frequency arrhythmic electric state of abiological tissue the electric state of the biological tissue has to becaptured at least with regard to a dominant frequency of the highfrequency arrhythmic electric state. This will typically be achievedusing a sensor sensing the electric state of the biological tissue whichprovides an electric signal representative of the electric state of thebiological tissue, and using a determination unit determining thedominant frequency from the electric signal.

From the determined dominant frequency of the present electric state,the determination unit can then determine whether the present electricstate is a high frequency arrhythmic electric state of the biologicaltissue. If a high frequency arrhythmic electric state is determined, atleast one series of electric pulses is applied to the biological tissue.An electric pulse generator is provided for generating the at least oneseries of electric pulses at intervals depending on the at least onedominant frequency; and at least one electrode connected to the pulsegenerator is provided for applying the electric pulses to the biologicaltissue.

The inventors noticed that similar arrhythmic electric states of a samebiological tissue will sometimes be completely terminated and sometimesnot at all be terminated by same series of electric pulses. Further,they found that the success in terminating the arrhythmic electric stateis not a simple matter of probability, but that the electric chaosruling the arrhythmic electric state of the biological tissue does notdisplay a uniform level of disorganization over the time, but that thereis a continual coming and going of aspects of electric fieldcoordination between different areas of the biological tissue. The totalof this coordination shows a fluctuation with significant maxima. If theseries of electric pulses is applied to the biological tissue at a pointin time at which such a maximum coordination is reached, the probabilityof terminating the high frequency arrhythmic electric state of thebiological tissue is quite high, whereas it is quite low if the seriesof electric pulses is applied to the biological tissue in a minimumbetween two of these maxima. According to the interpretation of theinventors, which should however not be taken as a limitation to thepresent invention, the series of electric pulses starting at one of themaxima only has to provide for some more electric field coordination inthe biological tissue to terminate the high frequency arrhythmicelectric state, whereas, if applied in a minimum, the series of electricpulses has to start from zero in electrically coordinating thebiological tissue.

The inventors also found that the present total electric fieldcoordination within the biological tissue being in a high frequencyarrhythmic electric state can be assessed in that it is determined howdominant the dominant frequency is in the high frequency arrhythmicelectric state, a strong dominance of the dominant frequency indicatinga high total electric field coordination within the biological tissue.Particularly, the determination unit may determine from the electricsignal representative of the present electric state of the biologicaltissue a dominance level indicative of how dominant the at least onedominant frequency is in the high frequency arrhythmic electric state,and trigger the electric pulse generator to generate the at least oneseries of electric pulses starting at a point in time at which thedominance level exceeds a predefined threshold value.

In this way, the series of electric pulses is applied to the biologicaltissue at an optimum point in time with regard to the probability ofterminating the high frequency arrhythmic electric state. This alsomeans that the voltage and energy of the electric pulses applied at thisoptimum point in time may be lower than the voltage and energy of aseries of electric pulses applied at any other point in time, even ifthe same probability of terminating the high frequency arrhythmicelectric state is to be achieved. Thus, the method of the presentinvention is named Low Energy Antifibrillation Pacing (LEAP).

The predefined threshold value used for defining the optimum point intime for applying the series of electric pulses to the biological tissuemay be adjusted to the maxima of electric coordination typicallyoccurring within a particular biological tissue within any of its highfrequency arrhythmic electric states.

Particularly, the threshold value may be a percentage of a previouslyrecorded maximum value of the dominance level. In this way, thethreshold value is automatically adapted to the maximum dominance levelspresently occurring in the present high frequency arrhythmic electricstate. The percentage of the previously recorded maximum value of thedominance level may be adjusted to a suitable value within a typicalrange of 80% to 95%, like for example to 90%.

In determining the dominance level, the determination unit may filterthe electric signal for frequency components in a frequency rangeextending on at least one side of the dominant frequency. Preferably,the frequency range for which the determination unit filters extends onboth sides of the dominant frequency. Particularly, it may stretch fromabout a half of the dominant frequency to twice of the dominantfrequency. The concentration of the intensity of the electric signalwithin this frequency range on the dominant frequency is a very wellsuited criterion for assessing the electric coordination of thebiological tissue being in a high frequency arrhythmic electric state.

For determining the dominance level, the determination unit may comparethe intensity of the electric signal at the dominant frequency with theintensity of the electric signal at at least one neighboring frequency.The ratio of these intensities may be taken as the dominance level.Particularly, the intensity of the electric signal at the dominantfrequency may be compared with the intensity of the electric signal atat least one neighboring frequency in that an integral of theintensities of the electric signal within a frequency window includingthe dominant frequency and an integral of the intensities of theelectric signal within a frequency window including the neighboringfrequency are compared. Using such frequency windows will also have asmoothing effect on the dominance level in that noise is reduced bywhich the dominance level determined may be affected. Such a comparisonbetween the intensity of the electric signal at two differentfrequencies is easily accomplished in or close to real time.

The inventors also noticed that different biological tissues even of thesame kind show quite different electric propagation properties relevantin terminating a high frequency arrhythmic state of the biologicaltissue by applying a series of electric pulses. Particularly, thesedifferent electric propagation properties require different voltages orenergies of the electric pulses to achieve a certain probability ofterminating the high frequency arrhythmic electric state with one seriesof electric pulses. Thus, reaching a suitable probability of terminatingthe high frequency arrhythmic electric state with pulses of low voltageand energy requires assessing the actual electric properties of thebiological tissue. However, it is unsuitable to make this assessment bya simply trial and error procedure in which electric pulses of differentvoltage and electric energy are applied to the biological tissuepreviously voluntarily transferred into a high frequency arrhythmicelectric state. The inventors found that the electric propagationproperties of a biological tissue may be suitably assessed starting froma non-electrically excited base state of the biological tissue. In abeating heart, for example, such a non-electrically excited base stateis present between the individual heartbeats. If, in this electric basestate of the biological tissue, individual electric pulses of a sameduration but of different voltages are applied to the biological tissueand if electric signals sensed at the biological tissue after eachindividual electric pulse, i.e. in response to the individual electricpulse, are evaluated, the electric properties of the biological tissuecan be estimated for adjusting a minimum suitable voltage of theelectric pulses of the at least one series of electric pulses to begenerated by the electric pulse generator for successfully terminating afuture high frequency arrhythmic electric state of the biologicaltissue. The dependence of the response, particularly of the responsetime of the biological tissue to an individual electric pulse on thevoltage or electric field of the electric pulses applied may beevaluated as a power law. This power law allows for conclusions on thedistributions of heterogeneities in the biological tissue from whichwave emissions may be induced by the electric pulses of the series ofelectric pulses.

This assessment of the electric properties of the biological tissue maybe carried out in a set up mode of an apparatus for determining a highfrequency arrhythmic electric state of the biological tissue in whichthe electric pulse generator generates the individual electric pulses atthe same duration and at the different voltage taken from the sameranges and voltages which may be suitable for the electric pulses of theseries of electric pulses to be generated by the electric pulsegenerator for terminating a future high frequency arrhythmic electricstate of the biological tissue.

The dominant frequency of the high frequency arrhythmic electric statesalso defines a phase space of all potential phasings of electric wavesof that dominant frequency in the biological tissue. The phase spacedefined by the dominant frequency corresponds to a duration in theordinary time space which is equal to the reciprocal value of thedominant frequency or to its periodic time. To the end of terminatingthe high frequency arrhythmic electric state of the biological tissue, aseries of electric pulses is applied to the biological tissue whichraster scan the full phase space defined by the dominant frequency once.It is to be noted that both raster scanning the full phase space andonly scanning it once are relevant aspects of some embodiments of theapparatus and method of the present invention. Scanning it once ensureshitting each rotating wave contributing to the high frequency arrhythmicelectric state of the biological tissue in a vulnerable window of itsphasing. Scanning the full phase space not more than once avoidscreating a secondary high frequency arrhythmic electric state in thebiological tissue with the electric pulses applied. As raster scanningthe phase space means that every circular wave to be terminated issubjected to an electric pulse in its vulnerable window, the electricenergy of each electric pulse can be kept low without losing thenecessary efficacy within the vulnerable window. This low electricenergy of the single electric pulses also reduces the danger of creatinga secondary unwanted electric state of the biological tissue, as theelectric energy may simply be to low for this.

Whereas each series of electric pulses only raster scans the full phasespace defined by the dominant frequency once, more than one series ofelectric pulses may be applied to the biological tissue to terminate thehigh frequency arrhythmic electric state at intervals which are muchlonger than the intervals at which the electric pulses of one seriesfollow each other. Preferably, the intervals of the series are evenlonger than the duration of each single series of electric pulses.

The time intervals at which the single electric pulses of each series ofelectric pulses are generated have to be selected such that the phasespace defined by the at least one dominant frequency is raster scannedat sufficiently small phase intervals to hit every rotary wave in itsvulnerable window but with as low a total number of electric pulses aspossible.

Typically, the phase space should be raster scanned at phase intervalsin a range from π/16 to 2π/5, 2π been the dimensionless size of thephase space. Preferably, the phase space is scanned at phase intervalsin a range from π/5 to 2π/7 which means that about 7 to 10 individualpulses at equal intervals are needed to raster scan the full phase spaceonce. Generally, the intervals of the individual pulses do not need tobe equal. They may even be non-equal on purpose to avoid the excitationof any periodic electric states of the biological tissue. However, theymay be equal or at least about equal to uniformly raster scan the phasespace.

Actually, the electric pulses may be generated at time intervalsdeviating from the reciprocal value of the dominant frequency by adeviation in time in a range of 1/32 to ⅕, preferably from 1/10 to 1/7of the reciprocal value of the dominant frequency.

Generally, the electric pulses may be generated at intervals beingsmaller than the reciprocal value of the dominant frequency. Preferably,however, the intervals of the electric pulses exceed the reciprocalvalue by the deviation in time discussed above.

The time intervals and the phase intervals of the electric pulsesdiscussed above include the pulse duration of the electric pulses of theseries of electric pulses. This pulse duration should be selected toapply sufficient electric energy within the vulnerable window of therotating waves to be terminated at the electric field strength applied.On the other hand, this electric energy and thus the pulse durationshould be kept low. Actually, the duration per pulse is in a typicalrange of 2 to 25 ms. Preferably, it is in a range from 5 to 15 ms.

The electric field to be applied across the biological tissue in eachindividual pulse which is necessary to terminate the rotating waves intheir vulnerable window may be as low as 0.05 Volt/cm. 3 Volt/cm may beregarded as an upper limit for the electric field strength suitablyapplied for terminating a high frequency arrhythmic state of abiological tissue. The preferred range of the field strength is from 0.1to 1 Volt/cm.

As compared to a standard heart defibrillation energy, the electricpulses of the series of electric pulses may be in a typical range fromonly 1/400 to ½ at maximum. Preferably, the electric energy per pulse isin a range from 1/200 to ⅕, even more preferably it is in a range from1/100 to 1/10 of the standard heart defibrillation energy. Even if thetotal electric energy applied to the biological tissue over one fullseries of pulses equals the standard heart defibrillation energy whichis known to those skilled in the art, the potential damage to thebiological tissue is much lower as the energy is distributed over alonger period of time, and as the maximum currents flowing through thebiological tissue are, thus, much smaller.

The electric energy per pulse may even be reduced further, if aplurality of series of electric pulses is generated, and if the singleseries of electric pulses are applied to different electrodes tosuccessively create electric fields across the biological tissue indifferent spatial directions. This aspect accounts for the fact thatrotating waves making up a high frequency arrhythmic electric state of abiological tissue not only differ in their phasing but also in theirspatial orientation. Thus, they do not only have a vulnerable window inthe phase space but also in the three dimensional space. If thisvulnerable window in the three dimensional space and in the phase spacecan be met in the same time, a particularly low electric energy itsufficient to terminate the respective rotating wave.

To the end of only applying as low a number of electric pulses to thebiological tissue as necessary, it may be determined from the electricsignal which is representative of the electric state of the biologicaltissue whether the biological tissue is still in the arrhythmic electricstate after each series of the electric pulses applied. Only if thebiological tissue is still in the arrhythmic electric state, a furtherseries of electric pulses may be applied to the biological tissue.

According to the present invention, the voltage and energy of theelectric pulses of the series of the electric pulses applied toterminate a high frequency arrhythmic electric state of the biologicaltissue are kept as low as possible. Due to the measures described here,the voltage and energy of the pulses is nevertheless suitable forachieving a high probability of the desired termination with a singleseries of the electric pulses. Nevertheless, there is little use inapplying a high number of such series and staying with the same voltageand energy of the electric pulses. Instead, at least one further seriesof electric pulses may be generated at a higher voltage than a previousseries of electric pulses, to increase the probability of terminatingthe high frequency arrhythmic electric state of the biological tissuequickly. Damage to the biological tissue and pain to a patientcomprising the biological tissue may increase with the increasingvoltage of the electric pulses. However, there is a good justificationfor this, if the arrhythmic electric state can not be terminated withlow voltages.

Further, if it has to be noticed that, even after a number of series ofelectric pulses with increasing voltage, the biological tissue is stillin the arrhythmic electric state, a single electric pulse of a standardheart defibrillation energy may be generated and applied to thebiological tissue. This means that, if the arrhythmic electric statecannot be terminated by series of electric pulses of low voltage andenergy which only cause little to no damage and pain, a standarddefibrillation technique may be applied to ultimately terminate thearrhythmic electric state, which may otherwise be fatal to thebiological tissue and the entire organism comprising the biologicaltissue.

A criterion for the biological material being in a high frequencyarrhythmic electric state is the dominant frequency of the electricsignal representing the electric state of the biological tissue. A highfrequency arrhythmic electric state is characterized by a frequency in arange from about 5 to about 20 Hertz.

If there is more than one dominant frequency in the electric signalrepresentative of the electric state of the biological tissue, thehighest dominant frequency of the electric signal may be taken as thedominant frequency defining the phase space to be scanned by theelectric pulses.

The electric pulses may be applied between at least one electrode and ahousing of an electric pulse generator forming a counter electrode. Thishousing may also include the further parts of the apparatus forterminating a high frequency arrhythmic electric state of a biologicaltissue.

The electrode connected to the pulse generator, on the other hand, maybe a cardiac electrode. Particularly, it may be an intrathoracicelectrode. In another variant, it may be a brain electrode, particularlya non-intracerebral electrode.

In a further variant it may be a skeletal muscle electrode, particularlya non-subcutaneous electrode.

In one embodiment, the method of anti-fibrillation pacing disclosed hereis applied to suppress atrial fibrillation (AF) by delivering low energyanti-fibrillation pacing (LEAP) pulses to the fibrillating atrium. Aswith other electrical therapies that have been devised to suppress AF,the LEAP shocks must be applied outside of the ventricular “vulnerablewindow” to avoid shock-induced induction of ventricular fibrillation(VF) by the far-field LEAP pulses, i.e., the far-field pulses have to beprevented from being applied to the atria during the vulnerable periodof the ventricle to prevent the possible induction of VF. Note that theventricular vulnerable window is not the vulnerable window of therotating waves. Whereas a suitable pulse applied during the vulnerablewindow of a rotating wave will terminate the rotating wave, a pulseapplied during the vulnerable window of the ventricle may cause VF.

Because ventricular activation during AF typically is irregular, sensingof ventricular activity and synchronization of, for example, 5 far-fieldpulses can be problematic. To overcome this obstacle, the presentinvention teaches to pace the ventricle at a constant cycle length priorto the delivery of the LEAP, as well as during the LEAP, to capture andregularize a defined ventricular rhythm. The pacing stimuli may bedelivered using an indwelling pacing/sensing catheter placed in the apexof the right ventricle and unipolar recordings may be obtained from thecatheter. The activation recovery interval (ARI), as measured from theright ventricular unipolar electrogram prior to LEAP, will be used by acontroller that synchronizes the delivery of LEAP so that no LEAP pulsesare delivered during the vulnerable windows of the ventricle. Thecontroller may be imbedded in the same ICD-like device that houses theLEAP algorithms.

In other embodiments of LEAP, LEAP protocols are applied that areeffective at energies below the ventricular excitation threshold duringthe ventricular relative refractory period (i.e., the vulnerablewindow). Consequently, a ventricular pacing/sensing catheter is notrequired here.

Referring now in greater details to the drawings, FIG. 1 illustrates thebasic design of an apparatus 1 for terminating a high frequencyarrhythmic electric state of a biological tissue 2. In a housing 3indicated by a dashed line the apparatus 1 comprises a determinationunit 4 and an electric pulse generator 5. Both the determination unit 4and the electric pulse generator 5 are connected to a counter electrode6 forming part of the housing 3. The counter electrode 6 serves as acounter electrode to an electrode 7 of the determination unit 4, whichserves as a sensor providing an electric signal representative of theelectric state of the biological tissue 2. The determination unit 4determines any dominant frequency of the electric state of thebiological tissue 2 and selects the highest dominant frequency. If thishighest dominant frequency is indicative of a high frequency arrhythmicelectric state of the biological tissue 2, the determination unitactivates the electric pulse generator 5 to generate at least one seriesof electric pulses depending on the determined dominant frequency. Theseelectric pulses are applied to the biological tissue 2 between thecounter electrodes 6 and an electrode 8 to terminate the high frequencyarrhythmic electric state of the biological tissue 2.

FIG. 2 is a simplified block diagram indicative on the method executedwhen using the apparatus 1 according to FIG. 1. In a first step, theelectric state of the biological tissue is sensed with a sensorproviding an electric signal. The electric signal representative of theelectric state is then analyzed with regard to at least one dominantfrequency of the electric state. If this dominant frequency is acharacteristic range from 5 Hertz to 20 Hertz, a dominance level of thedominant frequency is also determined. Beginning at a point in time atwhich the dominant frequency is above a threshold value TS, electricpulses are generated depending on the dominant frequency. These electricpulses are then applied to the biological tissue. Afterwards, theelectric state of the biological tissue is sensed again as it is done,if the dominant frequency is not in the characteristic range.

FIG. 3 (a) shows a typical intensity distribution of an electric signalrepresentative of the present electric state of a biological tissueplotted over its frequency, if the biological tissue is in a highfrequency arrhythmic electric state. The intensity I is highest at adominant frequency f_(d) but there are also other frequencies ofconsiderable intensity. The concentration of the intensity I on thedominant frequency f_(d) fluctuates over time. The dominance level L_(d)of the dominant frequency f_(d) may be measured in that the integral ofthe intensity I over a frequency window including the dominant frequencyf_(d) is compared to an integral of the intensity I over a frequencywindow including a neighboring frequency f_(n) adjacent to the dominantfrequency f_(d). FIG. 3 (b) is a plot of the electric field coordinationC_(e) of the various areas of a biological tissue being in an arrhythmicelectric state over the time t. The dominance level L_(d) is a measureof this electric coordination C_(e) in the arrhythmic electric state.FIG. 3 (b) shows that the dominance level L_(d) fluctuates over time andshows maxima at a distance in time in the order of seconds. Arrows ofsame vertical lengths indicate a possible increase in electriccoordination of the biological tissue caused by a series of electricpulses applied to the biological tissue. If this series of electricpulses is applied when the dominance level is only low, the resultingoverall electric coordination will not exceed a determination level DLabove which the electric field coordination of the biological tissue isso high that the arrhythmic electric state is terminated. If, however,the series of electric pulses is applied at a point in time at which thedominance level L_(d) already is above the threshold value TV, theresulting overall electric field coordination becomes higher than thedetermination level DL. Thus, determining the dominance level L_(d) andtriggering the series of electric pulses when the dominance level L_(d)exceeds the threshold value TV strongly enhances the chances toterminate the arrhythmic electric state of the biological tissue with asingle series of electric pulses of a certain voltage and energy.

FIG. 8 A depicts a time series of an electrocardiogram (ECG) showingsuccessful termination of ventricular fibrillation in vivo at t=0 usinglow energy anti-fibrillation pacing (LEAP) pulses (N=5 pulses, pacingfrequency 6.5 Hz). FIG. 8 B represents the interval of the time seriesshown in A preceding the LEAP pulses. Black bars indicate time intervalsΔT, which were used to obtain spectra shown in FIG. 8 C. FIG. 8 C is aspectrogram of the time series shown in FIG. 8 B indicating temporalfluctuations of the spectral content of the signal. Each spectrum wascomputed using Fast Fourier Transform and a time window of a length ΔT.FIG. 8 D depicts a spectral entropy obtained from the spectrogram anddisplays corresponding fluctuations of the spectral complexity asobserved in FIG. 8 C. FIG. 8 E shows two representative spectra obtainedat times (1) (plotted with a solid line in FIG. 8 D) and (2) (plottedwith a dashed line in FIG. 8 D) as indicated in FIGS. 8 B-D with dashedvertical lines.

The spectral entropy depicted in FIG. 8 D is defined as follows:

$\text{?} = {{- \frac{1}{\text{?}}}{\sum\limits_{\text{?}}^{N}\; {\text{?}{\ln \left( \text{?} \right)}}}}$?indicates text missing or illegible when filed                    

wherein N is the total number of spectral bins, and p_(i) is anormalized power spectral density in the i-th spectral bin.

FIG. 4 is a simplified block diagram of a set up procedure of theapparatus shown in FIG. 1. This set up procedure is only carried outwhen the biological tissue is not in an electrically excited state. Suchan unexcited electric state of the biological tissue, however, is alsopresent between the individual heartbeats of a beating heart, forexample.

To this unexcited biological tissue individual electric pulses of a sameduration but of different voltages are applied, and an electric responseto the individual pulses, particularly a response time within which acertain electric potential is reached at a point distant to an electrodeby which the individual electric pulsed are applied, is sensed. Thedependency of these response times on the voltage of the individualelectric pulses is then used to draw conclusions regarding the electricfield propagation properties of the biological tissues and to setminimum voltages for suitable electric pulses of series of electricpulses to be applied to the biological tissue in future events of highfrequency arrhythmic electric states. With a heart defibrillationapparatus, the procedure according to FIG. 4 may only be carried outunder medical surveillance when implanting and setting up thedefibrillation apparatus. With low voltage individual pulses it may,however, also be carried out at certain intervals of time to update theminimum voltages for the electric pulses of the series of electricpulses to compensate for any changes in the electric propagationproperties of the biological tissue.

FIG. 5 shows, how a series of electric pulses A to H is generateddepending on the reciprocal value 1/f of the dominant frequency f. Theintervals Tp of the individual pulses A to H exceed the reciprocal value1/f by a deviation Δ which is ⅛ of the reciprocal value 1/f. FIG. 5 (a)shows the pulses in the time space, whereas FIG. 5 (b) depicts thepulses A to H in the phase space, where they raster scan the full phasespace of 2π at the dominant frequency exactly once at intervals I_(P) ofπ/4. Any rotating wave of the dominant frequency f has a vulnerablewindow in the phase space which is hit by one of the pulses A to Haccording to FIG. 5 (b).

FIG. 6 shows, how another series of electric pulses A to H is generateddepending on the reciprocal value 1/f of the dominant frequency f. Here,the intervals Tp of the individual pulses A to H fall short of thereciprocal value 1/f by a deviation Δ which is ⅛ of the reciprocal value1/f. FIG. 6 (a) shows the pulses in the time space, whereas FIG. 6 (b)depicts the pulses A to H in the phase space, where they also rasterscan the full phase space of 2π at the dominant frequency exactly onceat intervals I_(P) of π/4, but in a direction opposite to the pulses Ato H according to FIG. 5 (b).

FIG. 7 schematically shows a procedure used to synchronize far-fieldanti-fibrillation pacing (FF-AFP) with ventricular activity, representedby a ventricular action potential. Using the ARI (“x”) measured duringventricular pacing for 10 beats at a constant cycle length (S1S1=400ms), the vulnerable window (VW) is defined, where VWmin=ARI−20 ms andVWmax=ARI+20 ms. The timing for the 5 FF-AFP pulses (P1-P5) iscalculated for a constant P-P interval (e.g., 90 ms) so that P2 isdelivered 10 ms before VWmin and P3 is delivered at least 10 ms afterVWmax. P3 pre-empts the following S1 (S1*), and the next two pulses (P4and P5) fall within the absolute refractory period of the ventricle.

Many variations and modifications may be made to the preferredembodiments of the invention without departing substantially from thespirit and principles of the invention. All such modifications andvariations are intended to be included herein within the scope of thepresent invention, as defined by the following claims.

1. An apparatus for terminating a high frequency arrhythmic electricstate of a biological tissue, the apparatus comprising: at least onesensor for providing an electric signal representative of the presentelectric state of the biological tissue; a determination unit whichdetermines from the electric signal at least one dominant frequency ofthe present electric state of the biological tissue, and whichdetermines from the at least one dominant frequency whether the presentelectric state of the biological tissue is a high frequency arrhythmicelectric state; an electric pulse generator for generating at least oneseries of electric pulses at intervals depending on the at least onedominant frequency; and at least one electrode connected to the pulsegenerator for applying the electric pulses to the biological tissue;wherein the determination unit, for terminating a determined highfrequency arrhythmic electric state of the biological tissue, determinesfrom the electric signal a dominance level indicative of how dominantthe at least one dominant frequency is in the high frequency arrhythmicelectric state; and triggers the electric pulse generator to generatethe at least one series of electric pulses starting at a point in timeat which the dominance level exceeds a predefined threshold value. 2.The apparatus of claim 1, wherein the threshold value is adjustable. 3.The apparatus of claim 1, wherein the threshold value is a percentage ofa previously recorded maximum value of the dominance level.
 4. Theapparatus of claim 3, wherein the percentage is adjustable.
 5. Theapparatus of claim 1, wherein, for determining the dominance level, thedetermination unit filters the electric signal for frequency componentsin a frequency range extending on at least one side of the dominantfrequency.
 6. The apparatus of claim 1, wherein, for determining thedominance level, the determination unit compares the intensity of theelectric signal at the dominant frequency with the intensity of theelectric signal at at least one neighboring frequency.
 7. The apparatusof claim 1, wherein, in a set up mode which is only to be activated whenthe present electric state of the biological tissue is neither a highfrequency arrhythmic electric state nor any other electrically exitedstate, the at least one electrode applies the individual electric pulsesto the biological tissue; and the determination unit determines from theelectric signals provided by the at least one sensor in response to theindividual electric pulses a minimum suitable voltage of the electricpulses of the at least one series of electric pulses to be generated bythe electric pulse generator for successfully terminating a future highfrequency arrhythmic electric state of the biological tissue.
 8. Theapparatus of claim 7, wherein, in the set up mode, the electric pulsegenerator generates the individual electric pulses at the same durationin a range from 2 to 25 ms and at the different voltages in a range from0.05 to 3 V/cm.
 9. The apparatus of claim 1, wherein the electric pulsegenerator generates the electric pulses of the at least one series ofelectric pulses at such intervals and in such a number that the electricpulses raster scan a phase space defined by the at least one dominantfrequency once.
 10. The apparatus of claim 9, wherein the electric pulsegenerator generates the electric pulses of the at least one series ofelectric pulses at such time intervals that the electric pulses rasterscan the phase space defined by the at least one dominant frequency atphase intervals in a range from π/16 to 2π/5, preferably from π/5 to2π/7.
 11. The apparatus of claim 10, wherein the electric pulsegenerator generates the electric pulses of the at least one series ofelectric pulses at time intervals deviating from the reciprocal value ofthe at least one dominant frequency by a deviation in time in a rangefrom 1/32 to ⅕, preferably from 1/10 to 1/7, of the reciprocal value ofthe at least one dominant frequency.
 12. The apparatus of claim 11,wherein the electric pulse generator generates the electric pulses ofthe at least one series of electric pulses at intervals exceeding thereciprocal value.
 13. The apparatus of claim 1, wherein the electricpulse generator generates the electric pulses of the at least one seriesof electric pulses at a duration per pulse in a range from 2 to 25 ms,preferably from 5 to 15 ms.
 14. The apparatus of claim 1, wherein theelectric pulse generator generates the electric pulses of the at leastone series of electric pulses at such a voltage that each electric pulsecreates an electric field across the biological tissue in a range from0.05 to 3 V/cm, preferably from 0.1 to 1 V/cm.
 15. The apparatus ofclaim 1, wherein the electric pulse generator generates the electricpulses of the at least one series of electric pulses at an electricenergy per pulse in a range from 1/400 to ½, preferably from 1/200 to ⅕,and even more preferably from 1/100 to 1/10, of a standard heartdefibrillation energy.
 16. The apparatus of claim 1, wherein theelectric pulse generator generates a plurality of series of electricpulses, the electric pulses of each series of electric pulses rasterscanning the full phase space defined by the same at least one dominantfrequency once, and the single series of electric pulses of theplurality of series being applied to different electrodes connected tothe electric pulse generator to successively create electric fieldsacross the biological tissue in different spatial directions.
 17. Theapparatus of claim 1, wherein, after the electric pulse generatorgenerated any series of electric pulses, the determination unitdetermines from the electric signal whether the biological tissue isstill in the arrhythmic electric state, and wherein the electric pulsegenerator only generates any further series of electric pulses, if thebiological tissue is still in the arrhythmic electric state.
 18. Theapparatus of claim 17, wherein the electric pulse generator generates atleast one further series of electric pulses at a higher voltage than aprevious series of electric pulses.
 19. The method of claim 17, wherein,if the determination unit, after a predefined number of series ofelectric pulses, determines that the biological tissue is still in thearrhythmic electric state, the electric pulse generator generates asingle electric pulse of a standard heart defibrillation energy and; theat least one electrode applies the single electric pulses to thebiological tissue.
 20. The apparatus of claim 1, wherein thedetermination unit, in determining from the at least one dominantfrequency whether the biological tissue is in a high frequencyarrhythmic electric state, determines from the electric signal whether adominant frequency of the present electric state of the biologicaltissue is in a frequency range from 5 to 20 Hz.
 21. The apparatus ofclaim 1, wherein the determination unit determines the at least onedominant frequency of the present electric state of the biologicaltissue as the highest dominant frequency of the electric signal.
 22. Theapparatus of claim 1, wherein at least a part of a housing of theapparatus including the determination unit and the electric pulsegenerator forms a counter electrode connected to the pulse generator forapplying the electric pulses to the biological tissue.
 23. The apparatusof claim 1, wherein the at least one electrode connected to the pulsegenerator is a cardiac electrode.
 24. The apparatus of claim 23, whereinthe at least one electrode connected to the pulse generator is anintrathoracic electrode.
 25. The apparatus of claim 1, wherein the atleast one electrode connected to the pulse generator is a brainelectrode.
 26. The apparatus of claim 25, wherein the at least oneelectrode connected to the pulse generator is a non-intracerebralelectrode.
 27. The apparatus of claim 1, wherein the at least oneelectrode connected to the pulse generator is a skeletal muscleelectrode.
 28. The apparatus of claim 25, wherein the at least oneelectrode connected to the pulse generator is a non-subcutaneouselectrode.
 29. The apparatus of claim 1, wherein the at least one sensoris configured to provide an electric signal representative of thepresent electric state of an atrium of a heart, wherein the electrodeconnected to the pulse generator is configured to apply the electricpulses to the atrium, and wherein the apparatus further comprises: atleast one further sensor configured to provide a further electric signalrepresentative of an ventricular action potential of a ventricle of theheart; a further electric pulse generator configured to generateelectric pacing pulses; at least one further electrode connected to thefurther pulse generator and configured to apply the electric pacingpulses to the ventricle; and a synchronization unit configured tosynchronize the at least one series of electric pulses with the electricpacing pulses such that no electric pulse of the at least one series ofelectric pulses is applied in a vulnerable window during which theventricle is susceptible to shock-induced ventricular fibrillation. 30.An apparatus for terminating an atrial fibrillation of an atrium of aheart, the apparatus comprising: at least one sensor configured toprovide an electric signal representative of the present electric stateof the atrium; a determination unit configured to determine from theelectrical signal whether the present electric state of the biologicaltissue is an atrial fibrillation; an electric pulse generator forgenerating at least one series of electric low energy anti-fibrillationpacing pulses at intervals depending on the electrical signal; at leastone electrode connected to the pulse generator configured to apply thelow energy anti-fibrillation pacing pulses to the atrium; at least onefurther sensor configured to provide a further electric signalrepresentative of an ventricular action potential of a ventricle of theheart; a further electric pulse generator configured to generateelectric pacing pulses; at least one further electrode connected to thefurther pulse generator and configured to apply the electric pacingpulses to the ventricle; and a synchronization unit configured tosynchronize the at least one series of low energy anti-fibrillationpacing pulses with the electric pacing pulses such that no low energyanti-fibrillation pacing pulse of the at least one series of low energyanti-fibrillation pacing pulses is applied in a vulnerable window duringwhich the ventricle is susceptible to shock-induced ventricularfibrillation.
 31. The apparatus of claim 30, wherein the at least onefurther electrode and the at least one further sensor are combined inone indwelling pacing/sensing catheter configured to be placed in theventricle.
 32. A method of terminating a high frequency arrhythmicelectric state of a biological tissue, the method comprising: obtaininga electric signal representative of the present electric state of thebiological tissue; determining from the electric signal at least onedominant frequency of the present electric state of the biologicaltissue; determining from the at least one dominant frequency whether thepresent electric state of the biological tissue is a high frequencyarrhythmic electric state; determining from the electric signal adominance level indicative of how dominant the at least one dominantfrequency is in the high frequency arrhythmic electric state; generatingat least one series of electric pulses at intervals depending on the atleast one dominant frequency; and applying the electric pulses to thebiological tissue starting at a point in time at which the dominancelevel exceeds a predefined threshold value for the biological tissuebeing in a determined high frequency arrhythmic electric state.
 33. Themethod of claim 32, wherein the threshold value is a percentage of apreviously recorded maximum value of the dominance level.
 34. The methodof claim 32, wherein, in determining the dominance level, the electricsignal is filtered for frequency components in a frequency rangeextending on at least one side of the dominant frequency.
 35. The methodof claim 32, wherein, in determining the dominance level, the intensityof the electric signal at the dominant frequency is compared with theintensity of the electric signal at at least one neighboring frequency.36. The method of claim 32, and further comprising a set up step carriedout when the present electric state of the biological tissue is neithera high frequency arrhythmic electric state nor any other electricallyexited state, the set up mode comprising: generating individual electricpulses of a same duration and of different voltages; applying theindividual electric pulses to the biological tissue; sensing electricsignals at the biological tissue in response to the individual electricpulses; and determining from the electric signals a minimum suitablevoltage of the electric pulses of the at least one series of electricpulses to be generated by the electric pulse generator for successfullyterminating a future high frequency arrhythmic electric state of thebiological tissue.
 37. The method of claim 36, wherein, in the set upstep, the individual electric pulses are generated at a same duration ina range from 2 to 25 ms and at different voltages in a range from 0.05to 3 V/cm.
 38. The method of claim 32, wherein the at least one seriesof electric pulses is generated such as to raster scan a full phasespace defined by the at least one dominant frequency once.
 39. Themethod of claim 38, wherein the electric pulses of the at least oneseries of electric pulses are generated at such time intervals that theelectric pulses raster scan the phase space defined by the at least onedominant frequency at phase intervals in a range from π/16 to 2π/5,preferably from π/5 to 2π/7.
 40. The method of claim 39, wherein theelectric pulses of the at least one series of electric pulses aregenerated at time intervals deviating from a reciprocal value of the atleast one dominant frequency by a deviation in time in a range from 1/32to ⅕, preferably from 1/10 to 1/7, of the reciprocal value of the atleast one dominant frequency.
 41. The method of claim 40, wherein theelectric pulses of the at least one series of electric pulses aregenerated at time intervals exceeding the reciprocal value.
 42. Themethod of claim 32, wherein the electric pulses of the at least oneseries of electric pulses are generated at a duration per pulse in arange from 2 to 25 ms, preferably from 5 to 15 ms.
 43. The method ofclaim 32, wherein the electric pulses of the at least one series ofelectric pulses are generated at such a voltage that each electric pulsecreates an electric field across the biological tissue in a range from0.05 to 3 V/cm, preferably from 0.1 to 1 V/cm.
 44. The method of claim32, wherein the electric pulses of the at least one series of electricpulses are generated at an electric energy in a range from 1/400 to ½,preferably from 1/200 to ⅕, and even more preferably from 1/100 to 1/10,of a standard heart defibrillation energy.
 45. The method of claim 32,wherein a plurality of series of electric pulses are generated, theelectric pulses of each series of electric pulses raster scanning thephase space defined by the same at least one dominant frequency, andwherein the single series of electric pulses of the plurality of seriesare applied to different electrodes to successively create electricfields across the biological tissue in different spatial directions. 46.The method of claim 32, and comprising, after generating any series ofelectric pulses, determining from the electric signal whether thebiological tissue is still in the arrhythmic electric state, and onlygenerating any further series of electric pulses, if the biologicaltissue is still in the arrhythmic electric state.
 47. The method ofclaim 46, wherein any further series of electric pulses is generated ata higher voltage than the previous series of electric pulses.
 48. Themethod of claim 46, wherein, if the biological tissue is still in thearrhythmic electric state after a predefined number of series ofelectric pulses, is generated at a higher voltage than the previousseries of electric pulses, a single electric pulse of a standard heartdefibrillation energy is generated and applied to the biological tissue.49. The method of claim 32, and comprising, in determining from the atleast one dominant frequency whether the biological tissue is in a highfrequency arrhythmic electric state, determining from the electricsignal whether a dominant frequency of the present electric state of thebiological tissue is in a frequency range from 5 to 20 Hz.
 50. Themethod of claim 32, and comprising, in determining the at least onedominant frequency of the present electric state of the biologicaltissue, determining the at least one dominant frequency as the highestdominant frequency of the electric signal.
 51. The method of claim 32,wherein the electric pulses are applied to the biological tissue via atleast one electrode and a counter electrode.
 52. The method of claim 51,wherein the at least one electrode is a cardiac electrode which isplaced via a cardiac catheter.
 53. The method of claim 51, wherein theat least one electrode is a brain electrode which is placedextracranially.
 54. The method of claim 51, wherein the at least oneelectrode is a skeletal muscle electrode which is placed nonsubcutaneously.
 55. The method of claim 32, wherein the biologicaltissue is in an atrium of a heart, and wherein the method furthercomprises: obtaining a further electric signal representative of anventricular action potential of a ventricle of the heart; generatingelectric pacing pulses; applying the electric pacing pulses to theventricle; and synchronizing the at least one series of electric pulseswith the electric pacing pulses such that no electric pulse of the atleast one series of electric pulses is applied in a vulnerable windowduring which the ventricle is susceptible to shock-induced ventricularfibrillation.
 56. A method of terminating an atrial fibrillation of anatrium of a heart, the method comprising: obtaining a electric signalrepresentative of the present electric state of the atrium; determiningfrom the electric signal whether the present electric state of thebiological tissue is an atrial fibrillation; generating at least oneseries of electric low energy anti-fibrillation pacing pulses atintervals depending on the electric signal; obtaining a further electricsignal representative of an ventricular action potential of a ventricleof the heart; generating electric pacing pulses; applying the electricpacing pulses to the ventricle; generating at least one series ofelectric low energy anti-fibrillation pacing pulses at intervalsdepending on the electric signal; applying the low energyanti-fibrillation pacing pulses to the atrium; and synchronizing the atleast one series of low energy anti-fibrillation pacing pulses with theelectric pacing pulses such that no low energy anti-fibrillation pacingpulse of the at least one series of low energy anti-fibrillation pacingpulses is applied in a vulnerable window during which the ventricle issusceptible to shock-induced ventricular fibrillation.